It has been known that S1P receptors whose ligand is sphingosine 1-phosphate (hereinafter, abbreviated to “S1P”), are G protein-coupled type receptors and play an important role in vivo. The receptors are currently classified into 5 subtypes (S1P1, S1P2, S1P3, S1P4 and S1P5).
S1P3 receptors are expressed in the vascular endothelial cells or vascular smooth muscle cells in the cardiovascular system, and are known to receive extracellular S1P stimuli and be coupled with Gi to activate MAPK (Mitogen-activated protein kinase) such as ERK (extracellular signal-regulated kinase) or with Gq/G12 to activate Rho (Ras homologue). Thus, it has been suggested that the S1P3 receptors are associated with the progress of arteriosclerosis, intimal thickening, or vascular proliferative diseases such as solid tumors, diabetic retinopathy and the like. In fact, suramin which specifically inhibits S1P3 receptors appears to be curatively effective for the disease model of arteriosclerosis. Thus, it is suggested that an S1P3 receptor-specific antagonist is useful as a prophylactic or therapeutic agent for the disease (see Non-Patent Documents 1 to 8).
Furthermore, it has been observed that S1P3 receptors are also expressed in human cardiac muscle cells. S1P3 receptors induce the generation of inositol 3-phosphate (IP3) through the action of Gq, while IP3 in the cardiac muscle cells, which is induced by stimulating angiotensin II receptor, is believed to affect the development or progress of cardiac hypertrophy. Therefore, there is a possibility that S1P3 receptors may also affect cardiac hypertrophy. Moreover, while the production of S1P is increased under the hypoxic stress caused by ischemia during acute myocardial infarction, it is suggested that ischemic reperfusion disorder might be caused by Ca2+ overload involving S1P3 receptors. Therefore, an antagonist of S1P3 receptor is conceived to be useful as a prophylactic or therapeutic agent for cardiac hypertrophy or ischemic reperfusion disorder after acute myocardial infarction (see Non-Patent Documents 9 and 10).
Meanwhile, since the S1P3 receptors are specifically expressed in the smooth muscle cells in the basilar artery of rats or human coronary vessels, the role of the S1P3 receptors in these organs has been focused. In experiments using frontal basilar artery or coronary artery of dog, S1P exhibited dose-dependent vasoconstrictive effect through the action of Rho, suggesting that S1P may be a novel vasoconstrictor substance or spasm-inducing substance that acts through S1P3 receptors. Actually, the vasconstrictive action of S1P in the frontal basilar artery of dog was inhibited by suramin or an S1P3 receptor antisense. Therefore, it is indicated that S1P3 receptor antagonist is useful as a prophylactic or therapeutic agent for cerebrovascular spasm after subarachnoid hemorrhage, angina pectoris or myocardial infarction caused by coronary spasm, or as a vasodilator (see Non-Patent Documents 10 to 14).
It is also suggested that S1P3 receptors are possibly associated with the dose-dependent vasoconstrictive effect of sphingosylphosphorylcholine in the renal capillaries of rat or the proliferation of mesangial cells, and thus may play an important role on renal diseases such as glomerulonephritis. Therefore, an S1P3 receptor antagonist is also suggested to be useful in preventing the progress of progressive renal disorder (see Non-Patent Documents 15 to 18).
However, although it is reported that S1P promotes the expression of tissue factor (TF) in the endothelial cells through the action of ERK, S1P together with thrombin also induces the expression of S1P3 receptors, and thus it is suggested that S1P and S1P3 receptors operate as a positive feedback mechanism for the promotion of TF expression. Therefore, it is suggested that S1P3 receptors could also be involved in the thrombus formation in thrombosis (see Non-Patent Document 19).
Moreover, the relationship between the S1P3 receptors and pulmonary diseases, atrial fibrillation or bradycardia has also been known. For example, while S1P is increasingly produced in the trachea due to inflammatory cytokines, S1P administered through the trachea in mice synergistically affects with TNF to cause pulmonary edema, which is caused by rapid opening of the tight junction through the function of the S1P3 receptor, as indicated from an experiment using an S1P3 receptor knockout mice. Therefore, it is suggested that S1P3 receptor antagonist is useful as a prophylactic or therapeutic agent for pulmonary diseases caused by pulmonary edema (adult respiratory distress syndrome (ARDS) and the like) (see Non-Patent Document 20).
In another experiment using the S1P3 receptor knockout mice, it has been also suggested that S1P possibly activates acetylcholine-sensitive K+ current (IK, ACh) through the action of S1P3 receptors to cause a delay of sinoatrial node pacemaker, thereby resulting in bradycardia. Furthermore, the activation of IK, ACh leads to parasympathetic-mediated atrial fibrillation, and thus S1P3 receptor antagonist is suggested to be useful as a prophylactic or therapeutic agent for bradycardia or parasympathetic-mediated atrial fibrillation (see Non-Patent Document 21).
As can be seen from the above, S1P3 receptor antagonist is useful as a prophylactic or therapeutic agent for arteriosclerosis; intimal thickening; vascular proliferative diseases such as solid tumors, diabetic retinopathy and the like, cardiac failure; ischemic reperfusion disorder; cerebrovascular spasm after subarachnoid hemorrhage; angina pectoris or myocardial infarction caused by coronary spasm; progressive renal disorders such as glomerulonephritis; thrombosis; pulmonary diseases caused by pulmonary edema (ARDS and the like); bradycardia; parasympathetic-mediated atrial fibrillation and the like, or as a vasodilator.
Antagonist for S1P3 receptors includes suramin or S1P3 antisense as described above.
However, suramin has a molecular weight of more than 1200, and thus may exhibit poor oral absorption. Antisense has a problem in large-scale preparation, and the efficiency of introducing thereof is yet insufficient for pharmaceutical application. Phenylquinolinecarboxamide derivatives (see Patent Document 1) and aminophenylpropionic acid derivatives (see Patent Document 2) are disclosed as S1P3 receptor antagonists of low molecular weight. Thiazolidine derivatives and thiazinane derivatives (see Patent Document 3), and arylamide derivatives (see Patent Document 12) are also disclosed as a compound having antagonistic function against S1P1 and S1P3 receptors. However, these compounds have not been used hitherto for clinical application. Other compounds exhibiting S1P receptor non-selective antagonistic action have been disclosed (see Patent Documents 4 to 7); however, the effect of these compounds on the S1P3 receptors is not known. As discussed in the above, S1P3 receptor-selective antagonist which is clinically applicable has been desired heretofore.
Meanwhile, as for examples of a compound having an arylamidrazone skeleton as the compound of the present invention does, Patent Document 8 discloses a compound represented by the following formula (A):

wherein R1 and R2, which are different, each represent a hydrogen atom, a methyl group or the like; R3 represents a hydrogen atom, a halogen atom or the like; R4 represents a hydrogen atom, a halogen atom, a nitro group or the like; and X represents an alkoxy group, an amino group or the like. Furthermore, Patent Document 9 discloses a compound represented by the following formula (B):

wherein R1 represents a hydrogen atom, an alkyl group or the like; R2 represents a hydrogen atom, a nitro group or the like; R3 represents a hydrogen atom, a halogen atom or the like; and X represents a methyl group, an alkoxy group, an amino group or the like. Non-Patent Document 22 discloses a compound represented by the following formula (C):

wherein R1 represents a halogen atom, a methyl group or the like; and R2 represents a hydrogen atom, a halogen atom or the like. However, none of the above-documents discloses the data indicating a specific antagonistic action against S1P3 receptors as shown in the present application. Moreover, Non-Patent Document 23 discloses a compound represented by the following formula (D):

wherein 1 represents an integer of 0 or 1; when l is 0, R1 represents a hydrogen atom, a 2-methyl group, a 4-methyl group, a 4-methoxy group or a 4-ethoxy group; and when l is 1, R1 represents a hydrogen atom. However, this document only provides a method for synthesizing a hydrazidine derivative from ethyl acetoacetate, and the compound (D) is described only in the Preparative Example, without any description on what effect the compound would have on S1P3 receptors.
Furthermore, Patent Documents 10 and 11 describe a compound having an arylamidrazone skeleton as an intermediate for obtaining a target substance, but the documents do not disclose any data suggesting a specific antagonistic action on the S1P3 receptors as shown in the present application.
[Patent Document 1] JP-A-2002-332278
[Patent Document 2] JP-A-2005-247691
[Patent Document 3] WO 03/062392
[Patent Document 4] JP-A-2002-212070
[Patent Document 5] JP-A-2003-137894
[Patent Document 6] WO 03/040097
[Patent Document 7] WO 02/064616
[Patent Document 8] WO 92/19588
[Patent Document 9] JP-A-62-45568
[Patent Document 10] JP-A-54-3071
[Patent Document 11] DE 2724819 A
[Patent Document 12] WO 2006/063033
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